Carvedilol In Heart Failure Research Articles

Fast up Titration of Carvedilol in Heart Failure Is Safe and Allow Discharging Patients with Full Dosage and the Identification of Those with Worse Prognosis

Fast up Titration of Carvedilol in Heart Failure Is Safe and Allow Discharging Patients with Full Dosage and the Identification of Those with Worse Prognosis

Prophylactic pacemaker use to allow β-blocker therapy in patients with chronic heart failure with bradycardia

Although the benefits of beta-blocker therapy for patients with congestive heart failure (CHF) are independent of pretreatment heart rate, patients with chronic systolic heart failure and low resting heart rates are often excluded from beta-blocker therapy. We investigated the effectiveness and cost-effectiveness of prophylactic pacemaker insertion to facilitate beta-blocker use in these patients. A Markov model simulated the natural history of a cohort of clinically stable patients with CHF (ejection fraction < or = 35%, mean age 60 years) with resting heart rates of < 68 beat/min. Two strategies were evaluated: (1) conventional therapy (conventional)-the risks for death and hospitalization were derived from the angiotensin-converting enzyme inhibitor arm of the SOLVD treatment trial; and (2) pacemaker insertion with atrial pacing and carvedilol therapy (pacemaker-carvedilol)-risk reductions for death and CHF-related hospitalizations for carvedilol compared with conventional therapy were derived from the US Carvedilol Heart Failure Study. We assumed full carvedilol benefits for 2 years, declining benefits for the next 3 and no additional benefits after 5 years, whereas pacemaker-related adverse events persisted. In the base case, the pacemaker-carvedilol strategy increased mean survival by 1.3 years at an incremental cost of $7800, for an incremental cost-effectiveness of $6100 per year of life saved. Results were most sensitive to theoretical pacing-induced harm, changes in hospitalization cost, and reductions in beta-blocker benefits. Prophylactic pacemaker insertion to facilitate beta-blocker treatment in patients with CHF with low resting heart rates has the potential to produce clinical benefits in a highly cost-effective manner.

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis

ABSTRACTBackground: Although β.blocker therapy has been shown to improve survival in patients with chronic heart failure, this class of drugs tends to be underutilized in diabetic patients due to concerns about adverse metabolic effects, especially on glycemic control. No randomized clinical trial has specifically evaluated the effect of β.blocker therapy on mortality in diabetic patients with heart failure. Previous meta. analyses combining results of heart failure trials with pharmacologically diverse β.blockers suggest that the survival benefit in diabetic patients may be diminished compared to benefits in non.diabetic patients. However, some trial results indicate that carvedilol, which blocks β1., β2., and α1.receptors and is a potent antioxidant, may produce at least comparable effects in both patient groups.Objectives: To evaluate the effect of carvedilol in patients with heart failure and diabetes, specifically to determine if the survival benefit of carvedilol demon- strated in heart failure trials was as great in the subgroups of patients with diabetes.Methods: A meta-analysis was performed that included 5757 patients with heart failure, 25% of whom had diabetes, from seven large placebo-controlled randomized trials with carvedilol. All large (> 100 patients) placebo-controlled, randomized trials with carvedilol in heart failure were included. The endpoint of all-cause mortality was examined in the overall population, patients without diabetes, and patients with diabetes. The number of patients needed to treat (NNT) for 1 year to prevent one death associated with carvedilol use in diabetic versus non-diabetic patients was also calculated. The log-rank test and the Cox proportional hazards regression were used to compare the event time distributions of carvedilol versus placebo with respect to the outcome of mortality.Results: Similar survival benefits were seen with carvedilol use in diabetic and non-diabetic patients (relative risk reductions of 28% [95% confidence interval (CI) 3-46%; p = 0.03] and 37% [95% CI 22-48%; p < 0.001], respectively). There were no significant differences between the relative mortality risk reductions or the NNT with carvedilol use in diabetic versus non- diabetic patients. The NNT for 1 year to prevent one death was 23 for all patients, as well as for non-diabetic patients, and 25 for the diabetic group.Conclusions: This meta-analysis provides evidence that the same survival benefit may occur with carvedilol in heart failure patients with and without diabetes. The low NNT in the severe heart failure trial, COPERNICUS, and the diabetic subgroup in this meta-analysis suggests that severe heart failure patients and heart failure patients with diabetes may particularly derive benefit from therapy with carvedilol.

Carvedilol blocks β2- more than β1-adrenoceptors in human heart

Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart β1- and β2-adrenoceptors. Methods: The positive inotropic effects of noradrenaline (in the presence of the β2-selective antagonist ICI118551) and adrenaline (in the presence of the β1-selective antagonist CGP20712), mediated through β1- and β2-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. Results: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at β2-adrenoceptors (−logKB=10.13 ± 0.08) than of noradrenaline at β1-adrenoceptors (−logKB=9.02 ± 0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to β1-blocker-treated patients, consistent with persistent preferential blockade of β2-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (ICa,L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both β-blockers from the receptors. Conclusions: Carvedilol blocks human cardiac β2-adrenoceptors more than β1-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of β-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue.

Carvedilol blockade of α 1- and β-adrenoceptor induced inotropic responses in rats with congestive heart failure

Carvedilol is a combined α 1- and β-adrenoceptor antagonist. We investigated the ability of carvedilol to antagonize functional effects mediated through myocardial α 1-adrenoceptors in failing vs. non-failing (sham-operated) control hearts and compared such antagonisms to those of myocardial β-adrenoceptors. Congestive heart failure was induced in Wistar rats by coronary artery ligation. Papillary muscles experiments were performed. Carvedilol antagonized inotropic effects mediated through myocardial α 1-adrenoceptors with similar potencies in failing (p K i = 7.7 (95%, CI; 7.4–8.0)) and sham-operated hearts (p K i = 7.9 (95%, CI; 7.6–8.1)). The potency for the α 1-adrenoceptors was 10–30-fold lower than that for the β-adrenoceptors. In failing hearts, the α 1-adrenoceptor mediated response was similar in size to the attenuated β-adrenoceptor mediated inotropic response. The β-adrenoceptor mediated lusitropic effects were not, however, attenuated in failing compared to sham-operated hearts. A low degree of α 1-adrenoceptor blockade in the myocardium may contribute to the beneficial effects of carvedilol in heart failure.

Demographics, Clinical Characteristics, and Outcomes of Patients Hospitalized for Decompensated Heart Failure: Observations From the IMPACT-HF Registry

Background Hospitalizations for decompensated heart failure are frequent. The Initiation Management Pre-discharge Assessment of Carvedilol Heart Failure (IMPACT-HF) registry collected observational data in patients hospitalized for worsening heart failure to characterize an unselected group of patients and to confirm the generalizability of the IMPACT-HF main trial population. Methods and Results The IMPACT-HF registry was conducted concurrently with the IMPACT-HF study, a randomized trial of in-hospital initiation of carvedilol compared with the standard practice of postdischarge β-blocker initiation. Patients were eligible for registry enrollment if they were hospitalized for heart failure regardless of ejection fraction. There were no exclusions to participation. Patients were followed for 60 days. The IMPACT-HF Registry enrolled 567 patients. The mean age was 71 years, 52% of the patients were men and 82% were Caucasian. At discharge, 71% received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 41% received digoxin, and 62% received β-blockers. The 60-day rate of rehospitalization or death was 31%. Conclusion The IMPACT-HF registry enrolled elderly patients admitted for worsening heart failure primarily resulting from progressive volume overload. The 60-day rate of death or rehospitalization was high despite the use of evidence-based therapies. New treatments for this population are needed to decrease the morbidity and mortality associated with decompensated heart failure.

Impact of a Standardized Titration Protocol with Carvedilol in Heart Failure: Safety, Tolerability, and Efficacy—A Report from the GESICA Registry

Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studied whether a standardized protocol for the initiation and titration of the beta-blocker carvedilol in a multicenter, open-label program would optimize beta-blocker use in heart failure (HF) patients. The program included: (1) the carvedilol initiation and titration period, and (2) long-term follow-up at 6 and 12 months. Of 1299 patients in the registry, 504 were excluded due to current therapy; of the remaining 795 eligible patients, 293 were excluded due to contraindications. Of the included patients with follow-up data (n = 316), 93.3% tolerated carvedilol initiation and 47.7% of the patients reached the target dose of 50 mg/day for a mean dose of 39 mg/day. Rates were comparable in the elderly (n = 83), of which 53% achieved a target dose for a mean dose of 43.08 mg/day. This protocol improved therapy rates and achieved target doses quickly (average of 4 visits). Concomitant medications did not have to be adjusted and there were low withdrawal rates (10%) and hospital admissions (7.2%) for HF. Patients were able to maintain carvedilol therapy at 6 and 12 months. These results indicate that a standardized titration protocol, as used in GESICA, for the initiation and titration of beta-blockers is well tolerated and may improve beta-blocker use in carefully selected heart failure patients.

Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca 2+-ATPase 2 gene transcription through modification of Sp1 binding

Carvedilol is a β-adrenoceptor blocker and a potent antioxidant that improves cardiac function in patients with heart failure. The restoration of sarcoplasmic reticulum Ca 2+-ATPase (SERCA2) gene expression may be an underlying mechanism of its beneficial effects on cardiac function. In primary cultured neonatal rat cardiac myocytes, treatment with either carvedilol or its β-receptor inactive metabolite, BM910228, attenuated the hydrogen peroxide-mediated decrease in SERCA2 mRNA and protein levels, while metoprolol, a pure β-blocker, had no effect. Moreover, carvedilol itself significantly enhanced SERCA2 gene transcription, suggesting that carvedilol specifically restores SERCA2 gene transcription. Site-directed mutagenesis revealed that two Sp1 sites in the SERCA2 gene promoter region mediated the response to carvedilol under oxidative stress. Further, electrophoretic mobility shift assays revealed that Sp1 and Sp3 transcription factors correlated with carvedilol-mediated changes in the promoter assays. These studies may provide a mechanistic explanation for the beneficial effects of carvedilol in heart failure.

Benefits of carvedilol for heart failure shown in community setting

Benefits of carvedilol for heart failure shown in community setting

β-blocker therapy for heart failure outside the clinical trial setting: Findings of a community-based registry

Background β-Blockers reduce morbidity and mortality rates in heart failure (HF) clinical trials, but it is unknown whether these findings persist in the community setting. Methods A registry was created to survey tolerability and outcomes during initiation and 1-year follow-up of β-blocker treatment with carvedilol in patients with HF treated by cardiologists (CARD) and primary care physicians (PCP) in the community. Results A total 4280 patients were enrolled (3121 by 259 CARD, 1159 by 129 PCP). Patient age averaged 67 ± 13 years; 35% were women and 12% were black. The left ventricular ejection fraction averaged 31 ± 12; New York Heart Association class was II-III in 86% and IV in 3%. Patients of PCP had higher left ventricular ejection fraction, were older, and more frequently were female, black, diabetic, hypertensive, and in New York Heart Association class III/IV. Minimal difficulty titrating carvedilol was noted by >80% of CARD and PCP. Significantly more CARD-treated patients reached carvedilol doses of 25 mg twice daily (49% vs 27%). Kaplan-Meier all-cause mortality rate was 8.5% at 1 year and did not differ between CARD-treated and PCP-treated patients (8.2% vs 9.3%, P = .254). At least one HF hospitalization occurred in 11% of patients during follow-up, compared with 28% in the preceding year. Conclusions Community-based physicians use carvedilol with success approaching that of clinical trials. Overall mortality rates and HF hospitalizations were in the same low range as in clinical trials. Thus, it appears that results of clinical trials with carvedilol for HF can be translated to the community setting.

Tolerability of carvedilol in heart failure: clinical trials experience

An extensive clinical trials database now exists to support the therapeutic efficacy of β-blockers in systolic heart failure. However, concerns remain about the tolerability of these agents. These concerns relate to perceived complexity in initiation and uptitration, risk of worsening heart failure clinical status, and delay in beneficial effects on outcomes. All of the above concerns are thought especially relevant in patients with advanced disease. However, these perceptions are not borne out in the controlled clinical trial experience or in open-label studies and postmarketing surveillance programs with carvedilol. Specifically, in clinical studies, discontinuation rates (because of adverse events), serious adverse event rates, mean achieved dose, and percentage reaching target dose strongly suggest good tolerability. This is especially notable, considering that β-blockade is used in addition to other background neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors. Furthermore, tolerability in the everyday community setting also appears to be high. Carvedilol, specifically, is also well tolerated during initiation of therapy, with fewer withdrawals for heart failure during the first 8 weeks of uptitration, and no delay in the accrual of beneficial clinical outcomes, as observed in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. Thus, in contrast to widely held perceptions about tolerability of β-blockade in heart failure, carvedilol appears to be an extremely well-tolerated agent, even during initiation and in the most advanced patients.

Landmark studies: the Australia/New Zealand Heart Failure Collaborative Group (ANZ) Trial and the US Carvedilol Trials Program

The safety, tolerability, and hemodynamic effects of carvedilol in patients with heart failure were first studied in the mid 1990s. Positive results in these early trials led to 5 prospective, randomized, double-blind, placebo-controlled trials—the Australia/New Zealand Heart Failure Collaborative Group (ANZ) study and the 4 component studies of the US Carvedilol Heart Failure Trials Program. These studies were conducted to determine the clinical impact of long-term carvedilol therapy. Findings from these trials showed that carvedilol is a powerful therapy (1) in patients with chronic heart failure caused by left ventricular (LV) systolic dysfunction, improving morbidity and mortality; and (2) in patients with symptomatic heart failure, improving LV ejection fraction, improving clinical status, and slowing disease progression, resulting in reduction of the combined risk of hospitalization and mortality. This article discusses the design, results, and clinical implications of these trials.

Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial1, *1

Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial1, *1

Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial

Background The efficacy and optimum dose of β-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a β-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF. Methods After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class. Results Carvedilol therapy achieved dose-dependent improvement of all end points ( P for linear trend, range .002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization ( P range, .024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events. Conclusions In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

Beta blockers improve outcome in patients with heart failure and atrial fibrillation: U.S. carvedilol study.

Atrial fibrillation (AF) is present in a significant number of patients with heart failure (HF) caused by left ventricular systolic dysfunction and is associated with increased morbidity and mortality. The deleterious interaction of AF and HF is mediated through a number of mechanisms including hemodynamic alterations and activation of the sympathetic nervous system. Beta-blockers have been shown to improve symptoms and survival in patients with HF. In addition, beta-blockers have been used in patients with AF, primarily for rate control. A retrospective analysis of the U.S. Carvedilol Heart Failure Trial demonstrated that carvedilol improves outcomes in the high-risk subgroup of patients with HF and concomitant AF.

Choosing metoprolol or carvedilol in heart failure (a pre-COMET commentary)

Choosing metoprolol or carvedilol in heart failure (a pre-COMET commentary)

Use of beta-blockers in congestive heart failure

While β-adrenergic blockers have been used for decades in a variety of cardiovascular illnesses, they have traditionally been avoided in chronic heart failure. In spite of significant advances in management, mortality in patients suffering from heart failure remains unacceptably high and new therapies are urgently needed. Recently, several large clinical trials have shown a significant reduction in both morbidity and mortality in heart failure patients when β-blockers are added to standard therapy. While further investigation is warranted in certain subgroups, the use of β-adrenergic blockers in New York Heart Association (NYHA) class II to IV heart failure should now be considered routine. The purpose of this article is to outline and review the five major clinical trials of β-blocker therapy in chronic heart failure; the US Carvedilol heart failure Program (USCP), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF), the Beta-blocker Evaluation of Survival Trial (BEST) and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS), and to aid the reader in the selection of appropriate candidates for β-blocker therapy.

Carvedilol: a review of its use in chronic heart failure.

Carvedilol (Dilatrend) blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors, and has antioxidant and antiproliferative effects. Carvedilol improved left ventricular ejection fraction (LVEF) in patients with chronic heart failure (CHF) in numerous studies. Moreover, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Carvedilol also reversed or attenuated left ventricular remodelling in patients with CHF and in those with left ventricular dysfunction after acute myocardial infarction (MI). Combined analysis of studies in the US Carvedilol Heart Failure Trials Program (patients had varying severities of CHF; n = 1094) revealed that mortality was significantly lower in carvedilol than in placebo recipients. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower with carvedilol than with placebo. Mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF in the Carvedilol Or Metoprolol European Trial (COMET) [n = 3029]. The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial (n = 2289) demonstrated that compared with placebo, carvedilol was associated with significant reductions in all-cause mortality and the combined endpoint of death or hospitalisation for any reason in severe CHF. All-cause mortality was reduced in patients who received carvedilol in addition to conventional therapy compared with those who received placebo plus conventional therapy in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (enrolling 1959 patients with left ventricular dysfunction following acute MI). Carvedilol was generally well tolerated in patients with CHF. Adverse events associated with the alpha- and beta-blocking effects of the drug occurred more commonly with carvedilol than with placebo, whereas placebo recipients were more likely to experience worsening heart failure. In conclusion, carvedilol blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors and has a unique pharmacological profile. It is thought that additional properties of carvedilol (e.g. antioxidant and antiproliferative effects) contribute to its beneficial effects in CHF. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe CHF, and should be considered a standard treatment option in this setting. Administering carvedilol in addition to conventional therapy reduces mortality and attenuates myocardial remodelling in patients with left ventricular dysfunction following acute MI. Moreover, mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred beta-blocker.